Gametogenesis in mammals is characterized by a precise succession of proliferative, meiotic, and cellular differentiation events. Meiosis occurs only in the gonads. In the mammalian male, spermatogenesis is an ongoing process in which stem cell proliferation, meiosis, and cellular differentiation occur concomitantly. These three processes are controlled by hormonal, paracrine, and genetic factors. Meiosis is one of the targets of the hormonal control. The identification of genetic controls of meiosis will provide information on the targets of action of the hormonal and paracrine controls of spermatogenesis. Some meiosis inducing and meiosis preventing activities have been described in various mammalian species but none of these have ever been fully characterized. Yeast are the only eukaryote in which proteins controlling meiosis have been full characterized both at the gene and protein levels. In Saccharomyces cerevisiae a cascade of repressive and inducer genes has been described. Since many cellular proliferation controls have been extremely well conserved from yeast to mammals, we propose to test the hypothesis that the Saccharomyces cerevisiae meiosis initiation cascade, or parts of it, has been phylogenetically conserved. Our preliminary data suggests that this is the case for at least one of such yeast peptides called Inducer of Meiosis 1 (IME1). This is the only initiator of meiosis gene that has been extensively characterized in eukariotes. Complementation experiments in our hands show that testicular cDNA's functionally complement an IME1 deficient yeast strain. Some of these complementing strains hybridize at low stringency with yeast IME1. Characterization of this human gene would: a) provide insight into a fundamental problem in cell biology; b) allow testing the role of this gene in cases of early meiotic arrest; c) offer the opportunity to interfere with meiosis induction without interfering with hormonal or paracrine controls; the only cells that would be affected are the meiotic gametes which are confined to the testes. The purpose of this proposal over the next five years is four fold: a) To sequence the complementing clones and fully characterize human IME1 (hu-IME1) and its protein product and confirm its restricted expression in early meiosis in both mice and monkey; b) to attempt cloning the human homologues of two other yeast meiosis entry control genes; c) to test the hypothesis that deletions or mutations involving hu-IME1 are responsible for some cases of early meiotic arrest, and d) to allow the primary investigator to acquire the factual knowledge, hands-on experience and intellectual skills to further his independent research in reproductive biology.